Department of Physics and Astronomy, University of Missouri, Columbia, Missouri 65211, United States.

Abstract

Two sets of ligand binding decoys have been constructed for the community structure-activity resource (CSAR) benchmark by using the MDock and DOCK programs for rigid- and flexible-ligand docking, respectively. The decoys generated for each complex in the benchmark thoroughly cover the binding site and also contain a certain number of near-native binding modes. A few scoring functions have been evaluated using the ligand binding decoy sets for their abilities of predicting near-native binding modes. Among them, ITScore achieved a success rate of 86.7% for the rigid-ligand decoys and 79.7% for the flexible-ligand decoys, under the common definition of a successful prediction as root-mean-square deviation <2.0 Å from the native structure if the top-scored binding mode was considered. The decoy sets may serve as benchmarks for binding mode prediction of a scoring function, which are available at the CSAR Web site ( http://www.csardock.org/).

The statistics of the ligand binding decoys for the CSAR benchmark: The number distribution of the near-native binding modes (RMSD<2.0 Å) in the (a) rigid-ligand and (b) flexible-ligand decoys of a complex; The maximum RMSD distribution in the (c) rigid-ligand and (d) flexible-ligand decoys of a complex. Notice that the horizontal axes in Panel (a) and Panel (b) are in logarithmic scales.

The flexible ligand binding decoys sampled by our docking method for the No.122 complex in set 1 (PDB code: 1UTO). The protein is represented by molecular surface. The ligand binding decoys are shown in semi-transparent, stick mode. The native ligand is shown in solid, stick mode and colored in magenta (C), blue (N) and gray (H). The figure was prepared using UCSF Chimera.

The success rates of ITScore, DOCK/FF, and DOCK/VDW on identifying native binding modes with the ligand decoys constructed for the CSAR benchmark when different criteria were used regarding the RMSD (Å) between the top-scored pose and the native structure. For each RMSD criterion, the bars correspond to ITScore, DOCK/FF and DOCK/VDW from left to right, respectively.

The RMSD values of the top binding modes predicted by ITScore (black, filled circle), DOCK/FF (red, filled diamond), and DOCK/VDW (blue, open circle) with set 1 of the CSAR benchmark: (a) rigid ligand decoys; (b) flexible ligand decoys. Notice that the CSAR ID numbers of the complexes are not sequential, and therefore the x axes extend up to 300, which is more than the total number of complexes.

The RMSD values of the top binding modes predicted by ITScore (black, filled circle), DOCK/FF (red, filled diamond), and DOCK/VDW (blue, open circle) with set 2 of the CSAR benchmark: (a) rigid ligand decoys; (b) flexible ligand decoys. Notice that the CSAR ID numbers of the complexes are not sequential, and therefore the x axes extend up to 300, which is more than the total number of complexes.